Abstract

Normal body cells grow, proliferate and die in an orderly manner. By contrast, cancer cells grow out of control and can invade
other tissues. The process of tumour progression and metastasis results from a complex molecular cascade that allows cancer
cells to leave the site of the primary tumour mass and disseminate to distant anatomical sites where they proliferate and
form secondary tumour foci. Disseminated disease is the most usual cause of death in cancer patients and is, therefore, a
very serious clinical problem. Transforming growth factor beta (TGF‐β) has a dual role in tumour progression, acting as a
tumour suppressor in early stages of carcinogenesis, and exerting a pro‐oncogenic role in the last steps of metastatic disease.
TGF‐β induces the epithelial mesenchymal transition of transformed cells, which contributes to tumour invasion and metastasis,
and is frequently overexpressed in cancer cells.

Key Concepts

TGF‐βs and their signalling components are widely expressed in all tissues and play a major role in human diseases.

The canonical signalling pathway triggered by TGF‐βs involves the activation of Smad proteins by the TGF‐β receptors and their
translocation into the nucleus. In addition, TGF‐β receptors can activate Smad‐independent (non‐canonical) pathways, including
MAPKs and Rho GTPases, among others.

Canonical and noncanonical TGF‐β signal transduction participates in and explains the broad spectrum of TGF‐β effects on tumour
progression.

TGF‐β is postulated as a dual factor in cancer since it can act either as a tumour suppressor in early stages of tumourigenesis
or as a tumour promoter in late stages of tumour progression.

One of the hallmarks at late stages of tumour progression is that cancer cells become refractory to the TGF‐β cell growth
inhibitory response.

Many types of cancer cells leaving primary carcinomas appear to depend on EMT to facilitate execution of most of the steps
of the invasion–metastasis process.

TGF‐β affects not only the tumour cells themselves but also the surrounding stroma by inhibiting cell adhesion, inducing immunosuppression
and angiogenesis, and by promoting the degradation of the extracellular matrix, further modulating the metastatic process.

By regulating TGF‐β expression and its canonical and noncanonical intracellular signalling, it may be possible to control
the tumour microenvironment, including angiogenesis, immunosurveillance escape and activation of stromal fibroblasts resulting
in cancer‐associated fibroblasts (CAFs), tumour‐stroma interactions and EMT.

Figure 1. TGF‐β signalling. TGF‐β ligands bind to their cognate cell surface type II receptor (TβRII) and to the type III receptor (TβRII),
inducing the activation of TGF‐β type I receptor (TβRI) and forming a heterotetrameric complex. Then, two sets of signalling
pathways can be stimulated/activated: (1) in the canonical Smad pathway (left), the activated receptor complex phosphorylates
the receptor associated‐Smads (R‐Smads) and the resulting phosphorylated R‐Smads interact with Smad4, forming a heteromeric
complex, which is translocated into the cell nucleus; and (2) in the non‐Smad pathway (right), the TGF‐β‐receptor complex
may activate the MAPK (ERK1,2, JNK, p38) or PI3K (AKT) routes. The activation of both Smad and non‐Smad signalling pathways,
in turn, initiates transcriptional or nontranscriptional activities to regulate cell behaviour and gene expression. Also,
a crosstalk between Smad and non‐Smad routes has been described. The inhibitory effect of I‐Smads is indicated. DTF, downstream
transcription factors.

Figure 2. TGF‐β in cancer. TGF‐β plays a dual role in human cancers, acting either as a tumour suppressor, in early stages, or as a
promoter of tumour metastasis in the late stage of tumour progression. The tumour‐suppressive activities of TGF‐β, including
inhibition of cell proliferation and induction of apoptosis, are observed in normal cells and early carcinomas. Conversely,
in the late stage of cancer TGF‐β displays pro‐oncogenic activities, such as induction of epithelial–mesenchymal transition
(EMT), which contributes to the increased migration and invasion of tumour cells. Also, the increment of TGF‐β within the
tumour affects the stroma microenvironment by promoting (1) angiogenesis; (2) increase of tumour‐associated immune cells (T‐cells,
neutrophils and macrophages, among others); (3) immunosuppression, allowing the tumour to escape host immunosurveillance;
(4) activation of fibroblasts to cancer‐associated fibroblasts (CAFs), which further support tumour growth and promote tumour
metastasis. ECM, extracellular matrix.

Figure 3. Therapeutic targeting of TGF‐β. TGF‐β can be targeted at different levels: (1) TGF‐β binding to its cellular receptors; (2)
signalling receptors, such ALK1 by monoclonal antibodies (mAbs) or ALK5 by small chemical inhibitors; (3) endoglin by humanised
mAbs; (4) TGF‐β expression can be downregulated by antisense oligo‐nucleotides (ODN); and (5) TGF‐β signalling can be inhibited
by ectopic expression using gene therapy of a dominant negative TβRII mutant.

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